Pharmaceutical compositions of orally active taxane derivatives having enhanced bioavailability

a technology of bioavailability and composition, which is applied in the direction of drug compositions, biocide, capsule delivery, etc., can solve the problems of high interpatient variability, unsatisfactory taste, and non-linear response in absorption versus dos

Inactive Publication Date: 2003-11-27
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although reports involving human clinical trials presented plasma levels of taxanes orally dosed in this manner, several disadvantages of this method of dosing were also described, including unpleasant taste, emesis, high interpatient variability, and non-linear response in absorption versus dose.

Method used

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  • Pharmaceutical compositions of orally active taxane derivatives having enhanced bioavailability
  • Pharmaceutical compositions of orally active taxane derivatives having enhanced bioavailability

Examples

Experimental program
Comparison scheme
Effect test

example 2

Capsule

[0036] Compound Ia was added to a batching vessel containing polyethylene glycol 400, Tween.RTM.80, and pre-melted polyethylene glycol 1450 and mixed at about 65.degree. C. to dissolve the drug and give a solution at 4% by weight. The solution was filled into size #0 gray, opaque hard gelatin capsules at 625 mg to provide a dosage form at a strength of 25 mg of the taxane derivative per capsule. Caps were placed on the filled capsule bodies after they were stored at room temperature for about 30-60 minutes to solidify the filled contents. The recommended storage condition for the capsules is 12 months at controlled room temperature of 15-25.degree. C. (59-77.degree. F.). The dosage form exhibits high potency recovery, rapid dissolution, and maintains excellent chemical, physical and dissolution stability during long-term storage, including no evidence of drug crystallization in the semi-solid matrix. Dissolution studies in water (in the absence of added surfactant) indicate t...

example 3

Capsule

[0037] Compound Ia was added to a batching vessel containing polyethylene glycol 400, pre-melted polyethylene glycol 1450 and pre-melted Gelucire.RTM. 44 / 14 and mixed at about 65.degree. C. to dissolve the drug and give a solution at 4%. by weight.

[0038] The solution was filled into size #1 gray, opaque hard gelatin capsules at 500 mg to provide a dosage form at a strength of 20 mg of the taxane derivative per capsule. Caps were placed on the filled capsule bodies after they were stored at room temperature, for about 30-60 minutes to solidify the filled contents. Capsules were dosed to each of 2 dogs at a dose of approximately 2 mg / kg and plasma samples were taken and analyzed for pharmacokinetic parameters including drug concentrations versus time. Absolute oral bioavailability and coefficient of variation were determined as described above in Example 1.

6 Percentage of Ingredient Amount (mg) Total Composition E Compound Ia 20.0 4.0% PEG 400 120.0 24.0% PEG 1450 120.0 24.0% G...

example 4

Capsule

[0039] Compound Ia was dissolved at 10% by weight in pre-melted Gelucire 44 / 14 at about 65.degree. C. and the solution was filled into size #1 gray, opaque hard gelatin capsules. Caps were placed on the filled capsule bodies after they were stored at room temperature for about 30-60 minutes to solidify the filled contents. Capsules were dosed to each of 3 dogs at a dose of approximately 3 mg / kg and plasma samples were taken and analyzed for pharmacokinetic parameters including drug concentrations versus time. The AUC's were calculated and used to determine the absolute oral bioavailability relative to Compound Ia administered intravenously to dogs from a PEG 400 solution.

7 Ingredient Amount (mg) Percentage of Total Composition F Compound Ia 30.0 10.0% Gelucire 44 / 14 270.0 90.0% Total 300.0 100.0% Pharmacokinetics F (Oral Bioavailability) 32.7% C.V. (Coefficient of Variation) 2%

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Abstract

Disclosed are pharmaceutical compositions which comprise an orally-active taxane derivative and a pharmaceutically acceptable solubilizing agent, and which provide effective and consistent oral absorption of the taxane derivative.

Description

[0001] This application claims priority benefit under Title 35 .sctn.119(e) of United States provisional Application No. 60 / 342,889 filed Dec. 20, 2001. The present invention relates to pharmaceutical compositions of orally effective taxane derivatives and to their use for inhibiting tumor growth in mammalian hosts. The compositions of the invention enable the production of dosage units that afford sufficient and consistent absorption of the taxane derivative, thereby providing safe and effective antitumor treatment.BACKGROUND OF THE INVENTION[0002] Taxanes are diterpene compounds having demonstrated antineoplastic activity. Taxanes such as paclitaxel (Taxol.RTM.) and docetaxel (Taxotere.RTM.), a semi-synthetic analog of paclitaxel, are clinically useful antitumor agents which impart a cytotoxic effect in vivo by a mechanism involving abnormal polymerization of tubulin and disruption of mitosis.[0003] These agents are commercially available in formulations adapted for intravenous ad...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61KA61K9/48A61K9/66A61K31/337
CPCA61K9/0019A61K9/4858A61K31/337A61K47/26A61K47/14A61K47/22A61K47/10A61P35/00A61K31/335
Inventor BOGARDUS, JOSEPH BALLARDPERRONE, ROBERT KEVINRAGHAVAN, KRISHNASWAMY SRINIVASVARIA, SAILESH AMILAL
Owner BRISTOL MYERS SQUIBB CO
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